FT-1101: A Structurally Distinct Pan-BET Bromodomain Inhibitor with Activity in Preclinical Models of Hematologic Malignancies

Members of the Bromodomain and Extra-Terminal (BET) family of bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) bind to acetylated lysine residues on histone tails and act as epigenetic readers to regulate chromatin structure and gene expression.  In particular, BET family member BRD4 has been shown to positively regulate the expression of MYC and other critical cancer-associated genes through the localization of BRD4 to super-enhancer regulatory elements.  Results from preclinical studies conducted using the small molecule tool BET inhibitor (+)-JQ1, and emerging data from clinical trials of BET inhibitors in leukemia and lymphoma patients, have provided support for the therapeutic potential of BET inhibitors in hematologic malignancies.

A protein structure-guided drug design approach was employed to explore small molecule acetyl lysine mimetics and led to the identification of the BET inhibitor FT-1101, which is structurally unrelated to reported clinical-stage BET inhibitors in the (+)-JQ1 class.  In biochemical binding assays, FT-1101 displayed equipotent inhibition of binding of both bromodomains in all four BET family members to a known bromodomain ligand (Kd ≤ 20 nM).  In vitro, FT-1101 displayed potent anti-proliferative activity across a broad panel of human leukemia, lymphoma, and multiple myeloma cell lines, with 66 out of 123 cell lines having IC₅₀ values < 500 nM.  For the MV-4-11 acute myeloid leukemia cell line, the anti-proliferative activity of FT-1101 (IC₅₀ = 40 nM) correlated with down-regulation of MYC gene and protein expression, suggesting that its anti-proliferative activity was at least in part due to suppression of MYC.  Additionally, genome-wide mapping of BRD4 super-enhancer binding sites in MV-4-11 cells by ChIP-sequencing identified several potential pharmacodynamic biomarkers outside of the MYC signaling network.

In vivo, in the MV-4-11 xenograft model, oral treatment with FT-1101 at its maximum tolerated dose resulted in significant tumor growth inhibition, including tumor regressions, on schedules ranging from once daily to once weekly, and similar activity was also observed in the THP-1 AML xenograft model.  Superior in vivo efficacy in the MV-4-11 model was observed for FT-1101 relative to BET inhibitors of the (+)-JQ1 class.  In vivo efficacy was associated with prolonged drug exposure and a >75% decrease in MYC gene expression in tumors that was sustained for at least 12 hours.  FT-1101 also crossed the blood-brain barrier in mice, achieving a pharmacologically relevant free drug concentration in the brain.

The promising preclinical profile of FT-1101 warranted its rapid progression into human clinical trials, and a Phase 1 study in patients with relapsed refractory acute leukemia or high-risk myelodysplastic syndrome is currently underway.